Members of the tumor necrosis factor receptor (TNFR) superfamily participate in a large number of events that regulate cell activation and programmed cell death. A substantial majority of signals induced by receptors of this family are delivered via cytoplasmic (CY) adapter molecules belonging to the TNFR- associated factor (TRAF) family. Although numerous reports have focused upon how the widely used TRAF2 molecule contributes to positive signals by most TNFR family molecules, little has been known about the functions of TRAF3, which shares a highly overlapping receptor binding site with TRAF2. It is now clear from work performed by our group and others during the past funding period that TRAF3 can play diverse, even sharply contrasting roles in signaling by different receptors. It has also been quite recently revealed that TRAF3 plays important roles in signaling by receptors of the innate immune system. To explore further the biological function of this understudied TRAF, this proposal will make use of a conditional TRAF3 deficient mouse strain, together with TRAFS-deficient cell lines, to understand the varied roles played by TRAF3 in B and T cell activation. This project investigates a molecule called TRAF3, expressed by several types of white blood cells, that contributes to the human immune response. A large variety of different molecules at the cell surface of white blood cells receive signals from the cell's environment, including other cells, and these receptors transmit information to the cell via various "messenger" molecules, including TRAF3. TRAF3 is expressed by all immune cells, and can deliver both positive (activating) and negative (regulatory) signals. To understand more about the signals delivered by TRAF3, as well as how the signals are delivered, we will study pairs of cells in which one member of the pair lacks TRAF3, as well as genetically altered mouse strains that lack TRAF3 specifically in one type of immune cell. The information to be gained can be used for small molecule drug design and other therapies that manipulate immunity in for vaccines, and treatment of autoimmune and malignant disease.